In the 1970s, a substance that has a weak growth hormone (GH)-releasing activity was found among opiate peptide derivatives (Non-Patent Document 1). Thereafter, more potent peptidyl growth hormone secretagogues (GHSs) were synthesized (Non-Patent Document 2). In the 1990s, a group of nonpeptidyl GHSs which shows GH-releasing activity after oral administration was synthesized (Non-Patent Document 3). GHSs collectively refer to a family of peptidyl and nonpeptidyl compounds having GH-releasing activity. Studies on the action mechanism thereof revealed that GHSs stimulate GH release by binding to a growth hormone secretagogue receptor (GHS-R), which differs from growth hormone-releasing hormone (GHRH) (Non-Patent Document 2).
In 1996, the GHS-R was identified by expression cloning using a nonpeptidyl GHS and found to be a G protein-coupled receptor (GPCR) based on the primary structure. However, GHS-R was an orphan receptor whose endogenous ligand was not identified (Non-Patent Document 4).
In 1999, a search for the endogenous ligand was carried out using a cell line stably expressing the GHS-R by monitoring increase in intracellular Ca2+ level. As a result, a substance that exhibits potent GH-releasing activity was isolated from the stomach and designated ghrelin (Non-Patent Document 5). Ghrelin is synthesized as a prepro form composed of 117 amino acid residues and secreted as a peptide composed of 28 amino acid residues after processing. The third serine residue (Ser3) at N-terminus is esterified with octanoic acid (fatty acid), and a peptide derived from the first four amino acids including the esterified serine at N-terminus exhibits physiological activity (Non-Patent Documents 5 and 6).
Ghrelin is predominantly expressed in the stomach and is also expressed in the intestinal tract, pancreas, and hypothalamus (Non-Patent Document 5). At present, GHS-R, which is a ghrelin receptor, is known to have two subtypes (1a, 1b). Subtype 1b lacks a C-terminal portion of 1a and does not actually function, whereas subtype 1a is widely distributed in many organs including the hypothalamus, pituitary, stomach, intestinal tract, heart, lung, pancreas and adipose tissue (Non-Patent Documents 7 to 9).
Ghrelin has multiple physiological functions in addition to GH-releasing activity from the pituitary, such as a potent orexigenic activity, regulation of energy metabolism, protective cardiovascular effects and stimulation of gastric motility and gastric acid secretion.
Ghrelin, which exhibits potent GH-releasing activity (Non-Patent Document 5 and 10), is a useful therapeutic agent for short stature, which is a growth-hormone-deficient disease. In addition, GH is thought to be a hormone that is closely related to aging as well as growth. In fact, a decrease in GH secretion causes loss of muscle and bone mass, resulting in impairment of QOL of the aged. Therefore, the GH-releasing activity of ghrelin is expected to ameliorate the GH-related dysfunctions, suggesting that ghrelin is useful as a prophylactic and therapeutic agent for aging.
Ghrelin is only a humoral factor showing a potent orexigenic activity by oral administration (Non-Patent Document 11). In human, the blood ghrelin level is high during fasting and decreases after a meal. Therefore, ghrelin is thought to be a hormone that initiates food intake (Non-Patent Document 12). Hunger signal has been elucidated to be transmitted to the feeding center via afferent vagal nerves from the stomach (Non-Patent Document 13). The potent orexigenic activity is expected to ameliorate eating disorders such as anorexia nervosa, suggesting that ghrelin is useful as a therapeutic agent therefor.
Subcutaneous daily administrations of ghrelin cause considerable weight gain and increase in the weight of adipose tissue, although food intake remains virtually unchanged (Non-Patent Document 14). Furthermore, subcutaneous administrations of ghrelin at high dose cause increase in respiratory quotient, suggesting increase in fat mass and suppressed utilization of body fat by ghrelin (Non-Patent Document 14). Thus, ghrelin is closely related to regulation of peripheral lipid metabolism and has function in regulating energy metabolism.
As described above, ghrelin shows anabolic effects, orexigenic effects, and regulatory effects on energy metabolism, which are associated with activation of GH-IGF1 (insulin-like growth factor 1) pathway by the GH-releasing activity. Therefore, ghrelin is useful as, for example, a therapeutic agent for cachexia (i.e., systemic wasting diseases involving anorexia, weight loss, muscle mass loss, fat loss, decreased muscle strength, etc.) caused by cancer, aging, serious heart failure, chronic obstructive pulmonary disease (COPD), infection, inflammatory disease, etc.; and a therapeutic agent for ameliorating hyposthenia caused by anorexia during chemotherapy (drug, e.g., anticancer agent) and radiotherapy.
Ghrelin has positive cardiovascular effects (Non-Patent Documents 15 and 16). Intravenous administration of ghrelin in patients with chronic heart failure reduces blood pressure and increases cardiac output without varing cardiac rate, clearly indicating amelioration of cardiac functions. In a post-heart-infarction heart failure model, ghrelin exhibits amelioration of cardiac functions and hypo-nutrition conditions (cachexia). This indicates utility of ghrelin as a therapeutic agent for heart failure (Non-Patent Document 17).
Ghrelin stimulates gastric motility via the vagal nerves (Non-Patent Document 18). This function is expected to provide a therapeutic agent for a disease involving a gastric motility disorder such as postoperative ileus or diabetic gastroparesis.
As described above, ghrelin or a GHS-R agonist is useful as a therapeutic agent for short stature; a therapeutic agent for aging; a therapeutic agent for eating disorder such as anorexia nervosa; a therapeutic agent for cachexia caused by cancer, aging, serious heart failure, chronic obstructive pulmonary disease (COPD), infection, inflammatory disease, etc.; a therapeutic agent for ameliorating anorexia during chemotherapy (drug, e.g., anticancer agent) and radiotherapy; a therapeutic agent for heart failure; and a therapeutic agent for postoperative ileus or diabetic gastroparesis.
From the aforementioned viewpoints, ghrelin or a GHS-R agonist has been investigated (Patent Documents 1 and 2). In fact, anamorelin hydrochloride represented by the following formula is known to be a useful agent for ameliorating cachexia (Patent Document 2).

A glucokinase-activating agent which is a compound having a dipeptide structure is reported (Patent Document 3). However, the document does not disclose the compounds of the present invention.